Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine
The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-i...
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Taylor & Francis Group
2025-12-01
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| Series: | Gut Microbes |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19490976.2024.2446423 |
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| author | Izabella Sall Randi Foxall Lindsey Felth Soren Maret Zachary Rosa Anirudh Gaur Jennifer Calawa Nadia Pavlik Jennifer L. Whistler Cheryl A. Whistler |
| author_facet | Izabella Sall Randi Foxall Lindsey Felth Soren Maret Zachary Rosa Anirudh Gaur Jennifer Calawa Nadia Pavlik Jennifer L. Whistler Cheryl A. Whistler |
| author_sort | Izabella Sall |
| collection | DOAJ |
| description | The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids. |
| format | Article |
| id | doaj-art-27c469da4dca423bb252269f742d8f56 |
| institution | Kabale University |
| issn | 1949-0976 1949-0984 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Gut Microbes |
| spelling | doaj-art-27c469da4dca423bb252269f742d8f562025-01-13T04:11:34ZengTaylor & Francis GroupGut Microbes1949-09761949-09842025-12-0117110.1080/19490976.2024.2446423Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphineIzabella Sall0Randi Foxall1Lindsey Felth2Soren Maret3Zachary Rosa4Anirudh Gaur5Jennifer Calawa6Nadia Pavlik7Jennifer L. Whistler8Cheryl A. Whistler9Department of Molecular, Cellular, & Biomedical Sciences, University of New Hampshire, Durham, NH, USADepartment of Molecular, Cellular, & Biomedical Sciences, University of New Hampshire, Durham, NH, USACenter for Neuroscience, University of California–Davis, Davis, CA, USADepartment of Molecular, Cellular, & Biomedical Sciences, University of New Hampshire, Durham, NH, USACenter for Neuroscience, University of California–Davis, Davis, CA, USACenter for Neuroscience, University of California–Davis, Davis, CA, USADepartment of Molecular, Cellular, & Biomedical Sciences, University of New Hampshire, Durham, NH, USADepartment of Molecular, Cellular, & Biomedical Sciences, University of New Hampshire, Durham, NH, USACenter for Neuroscience, University of California–Davis, Davis, CA, USADepartment of Molecular, Cellular, & Biomedical Sciences, University of New Hampshire, Durham, NH, USAThe therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.https://www.tandfonline.com/doi/10.1080/19490976.2024.2446423Microbiotaopioidanalgesic tolerancebutyrateshort-chain fatty acidinflammation |
| spellingShingle | Izabella Sall Randi Foxall Lindsey Felth Soren Maret Zachary Rosa Anirudh Gaur Jennifer Calawa Nadia Pavlik Jennifer L. Whistler Cheryl A. Whistler Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine Gut Microbes Microbiota opioid analgesic tolerance butyrate short-chain fatty acid inflammation |
| title | Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine |
| title_full | Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine |
| title_fullStr | Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine |
| title_full_unstemmed | Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine |
| title_short | Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine |
| title_sort | gut dysbiosis was inevitable but tolerance was not temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine |
| topic | Microbiota opioid analgesic tolerance butyrate short-chain fatty acid inflammation |
| url | https://www.tandfonline.com/doi/10.1080/19490976.2024.2446423 |
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